1. Field of the Invention
The present invention relates to a process for producing salts of cyanobenzylamines, and to the salts of cyanobenzylamines obtained by the process. The salts of cyanobenzylamines obtained according to the present invention serve as useful intermediates in the production of pharmaceuticals and agrochemicals.
2. Description of the Related Art
Conventionally, there have been known, for example, processes for producing salts of cyanobenzylamines, employing p-cyanobenzyl bromide as a starting material, as described below.
J. Org. Chem., 63 (1998) 19, 6715-6718 discloses a relevant process including reacting p-cyanobenzyl bromide with hexamethylenetetramine and, subsequently, reacting the reaction mixture with hydrogen chloride dissolved in ethanol.
J. Am. Chem. Soc., 81 (1959), 4328, discloses a process for synthesizing 4-aminobutyronitrile hydrochloride including reacting hydrazine with N-(3-cyanopropyl)phthalimide synthesized from 4-bromobutyronitrile; post-treating the resultant reaction product; and reacting the post-treated product in diethyl ether with anhydrous hydrogen chloride. The reference discloses that p-cyanobenzylamine hydrochloride is synthesized through a method similar to this method.
J. Med. Chem., 10 (1967), 833-840, discloses a process for producing p-cyanobenzylamine from xcex1-phthalimido-p-tolunitrile and hydrazine. The reference discloses synthesis of p-cyanobenzylamine hydrochloride, but does not disclose details of the method used for the synthesis.
Japanese International Application Domestic Publication No. 10-503477 discloses a process for synthesizing p-cyanobenzylamine hydrochloride including reacting hydrazine with N-(4-cyanophenyl)methylphthalimide prepared from p-cyanobenzyl bromide and potassium phthalimide; post-treating the resultant reaction product; and transforming the treated product into hydrochloride. However, the step of transforming the treated product into hydrochloride is not described in detail.
Japanese International Application Domestic Publication No. 9-509937 discloses a process for synthesizing p-cyanobenzylamine hydrochloride including reacting N-Boc-p-aminomethylbenzonitrile with hydrogen chloride gas in ethyl acetate.
In addition, identification of p-cyanobenzylamine as a hydrochloride thereof is reported in Chem. Ber., 34 (1901), 3368, but the identification method is not described.
Thus, these processes for producing salts of cyanobenzylamines are unsatisfactory as industrial production processes, since the processes require a number of reaction steps and attain an insufficient level of production yield.
In addition, the aforementioned references fail to disclose characteristic drawbacks arising during industrial production of cyanobenzylamine hydrochlorides. Specifically, problems in terms of product distribution, such as space required for storage and ease of transportation, and those in terms of production apparatus, such as vessels having the required capacity, are not identified, and the means for solving these problems have not been elucidated.
As far as the present inventors know, cyanobenzylamine hydrochlorides are bulky compounds, having bulk densities of 0.2 g/ml or less. The high bulkiness results in the necessity of providing an extensive area for storage in the case of industrial production and use of cyanobenzylamine hydrochlorides. Generally, suitable transportation means is chosen based on the weight of matter. However, when such bulky matter is handled, the forms of transportation means are limited because of the volume thereof. This is very disadvantageous in view of distribution costs. In addition, when a cyanobenzylamine hydrochloride is handled in a production apparatus, scaling-up the apparatus is needed, due to the low bulk density of the compound, increasing apparatus costs as well as causing inconvenience during operation.
Thus, it is an object of the present invention to provide an industrially suitable process for producing a salt of a cyanobenzylamine at high yield and in a simple manner. It is another object to provide a less-bulky salt of a cyanobenzylamine having a lower bulk density.
The present inventors have conducted extensive studies in order to solve the aforementioned problems, and have found that a salt of a cyanobenzylamine can be produced in a simple manner by reacting a cyanobenzylamine with an acid, and that, when the acid is used in the form of an aqueous solution, the produced cyanobenzylamine salt is endowed with a remarkably high bulk density as compared with a similar compound produced through a conventional process. On the basis of these findings, the inventors have further found that, by applying a salt of a cyanobenzylamine to the industrial production of chemicals, the distribution, including storage and transportation, as well as operability in relation to a production apparatus, can be remarkably improved. The present invention has been accomplished on the basis of the above findings.
Accordingly, the present invention provides a process for producing a salt of a cyanobenzylamine comprising reacting a cyanobenzylamine with an acid.
The invention also provides a salt of a cyanobenzylamine having a bulk density of 0.4 g/ml or more.
Upon the practice of the process of the invention, in general, a cyanobenzylamine may advantageously be reacted with an acid, optionally in a solvent, for a predetermined period of time while stirring, to thereby form a suspension of a salt of a cyanobenzylamine.
The cyanobenzylamines usable for the invention may preferably be compounds represented by the following formula. 
wherein X1, X2, X3 and X4 each independently represent a hydrogen atom, an alkyl group having 1 to 3 carbon atoms or a halogen atom, and the xe2x80x94CH2NH2 group may be at any position of ortho, metha or para to the xe2x80x94CN group.
Specific examples of the compounds may include unsubstituted cyanobenzylamines such as o-cyanobenzylamine, m-cyanobenzylamine and p-cyanobenzylamine, and substituted cyanobenzylamines such as 2-alkyl-4-cyanobenzylamine, 2-chloro-4-cyanobenzylamine, tetrafluorocyanobenzylamine and tetrachlorocyanobenzylamine.
Cyanobenzylamines can be produced through any of the known processes. For example, m-cyanobenzylamine and p-cyanobenzylamine can be readily synthesized through the process disclosed in Japanese Unexamined Patent Publication (kokai) No. 9-40630 by subjecting one nitrile group of isophthalonitrile and that of terephthalonitrile to reduction, respectively.
In the invention, cyanobenzylamine hydrates can also be employed as the starting material. Examples of the hydrates may include o-, m-, and p-cyanobenzylamine hydrates, with p-cyanobenzylamine hydrate being preferred.
Cyanobenzylamine hydrates can be produced through any of the known processes. For example, m-cyanobenzylamine hydrate and p-cyanobenzylamine hydrate can be readily synthesized through the process disclosed in Japanese Examined Patent Publication (kokoku) No. 40-10133, from m-cyanobenzylamine and p-cyanobenzylamine, respectively.
No solvent may be required in the reaction employed in the process of the invention. However, a solvent may be used so as to dilute the salt of a cyanobenzylamine to facilitate handling of the salt in the form of a suspension. Examples of preferred organic solvents may include toluene, ethyl acetate, and methylene chloride, which do not react with cyanobenzylamines or salts thereof and do not cause side reactions when the reaction system contains an acid. Such an organic solvent is used in an amount such that a salt of a cyanobenzylamine can be handled in the form of a suspension. Typically, the solvent may be used in an amount 0.1-10 times the mass of the employed cyanobenzylamine.
A preferred solvent to be employed in the process of the invention may be water. When water is used as a solvent, a salt, especially hydrochloride, of cyanobenzylamine having a bulk density of 0.4 g/ml or more can be obtained. Such a high-bulk-density cyanobenzylamine salt advantageously reduces distribution costs, particularly for industrial use.
Water serving as a solvent may be used in an amount such that the cyanobenzylamine salt can be handled in the form of a suspension. Preferably, water is used in an amount 0.1-10 times the mass of the employed cyanobenzylamine. When the amount is less than 0.1 times the mass, the formed suspension of the cyanobenzylamine salt may become more viscous, thereby causing problems such as difficulty in stirring during reaction, whereas when the amount is 10 times or more the mass, the formed cyanobenzylamine salt may dissolve in water, disadvantageously decreasing the yield.
When water is employed as a solvent in the process of the present invention, impurities contained in the cyanobenzylamine, that are difficult to remove through such purification methods as distillation, can be readily removed. Specifically, the impurities can be removed by utilizing the difference in solubility in water between the cyanobenzylamine salt and the impurity salts. Thus, a high-purity cyanobenzylamine salt can be obtained.
More specifically, when p-cyanobenzylamine is synthesized by reducing one nitrile group of terephthalonitrile (see, Japanese Unexamined Patent Publication (kokai) No. 9-40630) for example, p-xylylenediamine is by-produced in addition to the formed p-cyanobenzylamine. p-Xylylenediamine has a boiling point of 127.6xc2x0 C./590 Pa, and p-cyanobenzylamine has a boiling point of 132.4xc2x0 C./550 Pa. These two compounds are difficult to separate through distillation due to the small difference between their respective boiling points. In accordance with the present invention, when p-cyanobenzylamine containing p-xylylenediamine as an impurity is reacted with hydrogen chloride in water, high purity p-cyanobenzylamine hydrochloride can be obtained in the form of a solid, since the water solubility of p-cyanobenzylamine hydrochloride is much lower than that of p-xylylenediamine hydrochloride.
Where a cyanobenzylamine employed contains substances having a boiling point much higher than that of the cyanobenzylamine, such as tar-like substances, through the decomposition of the cyanobenzylamine, it is preferable that the high boiling point substances are preliminarily removed by distillation or the like before carrying out the process of the invention, since thereby a cyanobenzylamine salt of high crystallinity and high purity is obtained.
The acid to be employed in the invention is not particularly limited as far as it produces a salt of a cyanobenzylamine according to the process of the invention. Specific examples thereof may include hydrogen chloride, sulfuric acid, acetic acid, trifluoroacetic acid and propionic acid.
Where hydrogen chloride is employed as the acid, it may be in the form of gas or an aqueous solution. When hydrogen chloride gas is used, the gas itself, optionally diluted with an inert gas, is blown into a solution of the cyanobenzylamine, or alternatively, passed through a vapor phase cyanobenzylamine. The ratio of hydrogen chloride to an inert gas is not particularly limited.
When an aqueous solution of hydrogen chloride is used, the solution may be added dropwise to the cyanobenzylamine (or a solution thereof) or the cyanobenzylamine (or a solution thereof) may be added dropwise to the hydrogen chloride solution. No particular limitation is imposed on the concentration of hydrogen chloride in the solution, and an aqueous solution of hydrogen chloride industrially readily available may be used. Preferably, the concentration is 1-37 mass %, more preferably 5-37 mass %. When the concentration is low, the amount of filtrate during separation of the cyanobenzylamine hydrochloride from water through filtration increases, thereby increasing loss of the product due to dissolution and decreasing the product yield. In addition, it is difficult to achieve a concentration of 37 mass % or more with an industrially produced aqueous solution of hydrogen chloride.
Where the acid employed is a monobasic one such as hydrogen chloride, since the acid reacts with an amino group of the cyanobenzylamine in equimolar amounts, the amount of the acid may theoretically be equimolar to the cyanobenzylamine. However, the acid chloride is preferably used in an amount of 0.9-2.0 moles per 1 mole of the cyanobenzylamine in practice, since the cyanobenzylamine usually contains a certain amount of impurity.
Where the acid employed is a dibasic one such as sulfuric acid, a primary sulfate of the cyanobenzylamine is formed through the reaction of 2 moles of the cyanobenzylamine and 1 mole of sulfuric acid when sulfuric acid is used in an amount of 2/1 mole per 1 mole of the amino group in the cyanobenzylamine, and a secondary sulfate is formed through the reaction of the cyanobenzylamine and sulfuric acid in equimolar amounts when sulfuric acid is used in an amount of equimolar to the cyanobenzylamine.
The temperature of the reaction between a cyanobenzylamine and an acid is not particularly limited so long as the temperature is not lower than the melting point and not higher than the boiling point of the employed solvent. The reaction temperature is preferably 0-100xc2x0 C. in view of the operability and the like.
The cyanobenzylamine salt powder thus formed is separated from the suspension and dried, through a known method.
The present invention will be further illustrated below by way of examples, which should not be construed as limiting the invention thereto.
In the following examples, cyanobenzylamines and xylylenediamines were quantitated by means of high-performance liquid chromatography under the following conditions.
High-performance Liquid Chromatographic Analysis Conditions
Column: Shodex NN-614 (product of SHOWA DENKO K.K.)
Eluent: Mixture containing monosodium phosphate anhydrate (7.2 g), water (700 ml), and acetonitrile (300 ml)
Detector: UV detector
Hydrogen chloride was quantitated through anion chromatography under the following conditions.
Anion Chromatographic Analysis Conditions
Column: IonPac AS12A 4 mm (product of DIONEX)
Eluent: Aqueous solution containing sodium carbonate (2.7 mmol/l)+Sodium hydrogencarbonate (0.3 mmol/l)
The bulk density was measured with a Powder-tester Type PT-N (product of Hosokawa Micron).